Exploratory solid-phase synthesis of factor Xa inhibitors: discovery and application of p3-heterocyclic amides as novel types of non-basic arginine surrogates

J Z Ho; O E Levy; T S Gibson; K Nguyen; J E Semple

doi:10.1016/s0960-894x(99)00628-9

Exploratory solid-phase synthesis of factor Xa inhibitors: discovery and application of p3-heterocyclic amides as novel types of non-basic arginine surrogates

Bioorg Med Chem Lett. 1999 Dec 20;9(24):3459-64. doi: 10.1016/s0960-894x(99)00628-9.

Authors

J Z Ho¹, O E Levy, T S Gibson, K Nguyen, J E Semple

Affiliation

¹ Department of Medicinal Chemistry, Corvas International, Inc. San Diego, California 92121, USA.

PMID: 10617091
DOI: 10.1016/s0960-894x(99)00628-9

Abstract

A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3 d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b IC50 = 4.6 nM). The synthesis and biological activity of two focused libraries are reported.

MeSH terms

Amides / chemistry*
Arginine / chemistry*
Factor Xa Inhibitors*
Heterocyclic Compounds / chemistry*
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Amides
Factor Xa Inhibitors
Heterocyclic Compounds
Serine Proteinase Inhibitors
Arginine